ABSTRACT Colorectal cancer (CRC) incidence and mortality are rapidly rising in sub-Saharan Africa; CRC is now the 4th most common cancer in the World Health Organization-Africa region. This rising burden is mirrored in Nigeria, where more than half of patients die within one year of diagnosis. These statistics highlight the need for cost- effective, evidence-based prevention, screening, and treatment interventions in this limited-resource region. However, an understanding of risk factors and the genomic landscape of CRC in this population is needed to inform such efforts. Through the African Research Group for Oncology (ARGO), we have established infrastructure and local scientific partnerships for novel cancer studies in Nigeria. We have an existing clinical database and a biobank of tumor and matched normal blood specimens from 490 prospectively enrolled Nigerian CRC patients. Data suggest Nigerian CRCs may possess distinct etiology. Overweight/obesity, the most common CRC risk factor in the US, is ~3-fold less prevalent in Nigeria. Similarly, other established risk factors, such as smoking and alcohol use, are half as frequent in Nigeria, suggesting other common endemic factors (e.g., infectious agents, environment, or diet) may drive CRCs in Nigeria. Furthermore, our pilot sequencing data from 65 Nigerian tumors show clinically significant differences vs. US patients. For instance, tumors from Nigerian patients had ~2-fold fewer somatic APC mutations, more KRAS mutations, and ~3-fold higher prevalence of high microsatellite instability. We also found ~3-fold higher prevalence of hereditary Lynch syndrome in Nigerian patients. To extend these preliminary analyses and further define CRC etiology in Nigeria, we propose the first multi-center study of CRC risk factors and genomics in sub-Saharan Africa. We will use ARGO infrastructure to conduct a large, cost-efficient, opportunistic study to: 1) Identify risk factors for CRC in Nigeria. We will recruit 600 CRC cases matched to 1,200 cancer-free population-based controls. Participants will complete an existing questionnaire developed by our group for use in Nigeria to assess demographic, anthropometric, reproductive, lifestyle, dietary, and medical history. And 2) Characterize molecular features of CRC tumors in Nigeria. We will perform targeted deep sequencing of 468 established cancer genes in matched tumor/blood samples from a subset of 360 CRC cases enrolled in Aim 1. After combining with existing data from 65 patients (N=425), we will map cancer genes altered by somatic or germline mutations in Nigerian patients and compare our data to large existing US datasets. These aims will provide a better understanding of the risk factor and genomic features of CRC in a West African population ? a first step towards improving prevention, screening, and treatment of the disease in this understudied population. In addition, the etiological insights gained through the work proposed have high potential applicability to understudied US populations with poor CRC outcomes, such as African American and early-onset CRC patients.